Quinoline derivatives as neutrophil elastase inhibitors and their use

ABSTRACT

There are provided novel compounds of formula (I) wherein R 1 , R 3 , R 4 , R 5 , G 1 , G 2 , L and n are as defined in the Specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of neutrophil elastase.

FIELD OF THE INVENTION

This invention relates to novel quinoline derivatives, processes fortheir preparation, pharmaceutical compositions comprising them, andtheir use in therapy.

BACKGROUND OF THE INVENTION

Elastases are possibly the most destructive enzymes in the body, havingthe ability to degrade virtually all connective tissue components. Theuncontrolled proteolytic degradation by elastases has been implicated ina number of pathological conditions. Human neutrophil elastase (hNE), amember of the chymotrypsin superfamily of serine proteases is a 33-KDaenzyme stored in the azurophilic granules of the neutrophils. Inneutrophils the concentration of NE exceeded 5 mM and its total cellularamount has been estimated to be up to 3 pg. Upon activation, NE israpidly released from the granules into the extracellular space withsome portion remaining bound to neutrophil plasma membrane (See Kawabatet al. 2002, Eur. J. Pharmacol. 451, 1-10). The main intracellularphysiological function of NE is degradation of foreign organic moleculesphagocytosed by neutrophils, whereas the main target for extracellularelastase is elastin (Janoff and Scherer, 1968, J. Exp. Med. 128,1137-1155). NE is unique, as compared to other proteases (for example,proteinase 3) in that it has the ability to degrade almost allextracellular matrix and key plasma proteins (See Kawabat et al., 2002,Eur. J. Pharmacol. 451, 1-10). It degrades a wide range of extracellularmatrix proteins such as elastin, Type 3 and type 4 collagens, laminin,fibronectin, cytokines, etc. (Ohbayashi, H., 2002, Expert Opin.Investig. Drugs, 11, 965-980). NE is a major common mediator of manypathological changes seen in chronic lung disease including epithelialdamage (Stockley, R. A. 1994, Am. J. Resp. Crit. Care Med. 150,109-113).

The destructive role of NE was solidified almost 40 years ago whenLaurell and Eriksson reported an association of chronic airflowobstruction and emphysema with deficiency of serum α₁-antitrypsin(Laurell and Eriksson, 1963, Scand. J. Clin. Invest. 15, 132-140).Subsequently it was determined that α₁-antitrypsin is the most importantendogenous inhibitor of human NE. The imbalance between human NE andendogenous antiprotease is believed to cause excess human NE inpulmonary tissues which is considered as a major pathogenic factor inchronic obstructive pulmonary disease (COPD). The excessive human NEshows a prominent destructive profile and actively takes part indestroying the normal pulmonary structures, followed by the irreversibleenlargement of the respiratory airspaces, as seen mainly in emphysema.There is an increase in neutrophil recruitment into the lungs which isassociated with increased lung elastase burden and emphysema inα₁-proteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab.Invest. 75, 273-280). Individuals with higher levels of the NE-α₁protease inhibitor complex in bronchoalveolar lavage fluid showsignificantly accelerated decline in lung functions compared to thosewith lower levels (Betsuyaku et al. 2000, Respiration, 67, 261-267).Instillation of human NE via the trachea in rats causes lunghaemorrhage, neutrophil accumulation during acute phase andemphysematous changes during chronic phase (Karaki et al., 2002, Am. J.Resp. Crit. Care Med., 166, 496-500). Studies have shown that the acutephase of pulmonary emphysema and pulmonary haemorrhage caused by NE inhamsters can be inhibited by pre-treatment with inhibitors of NE (Fujieet al., 1999, Inflamm. Res. 48, 160-167).

Neutrophil-predominant airway inflammation and mucus obstruction of theairways are major pathologic features of COPD, including cystic fibrosisand chronic bronchitis. NE impairs mucin production, leading to mucusobstruction of the airways. NE is reported to increase the expression ofmajor respiratory mucin gene, MUC5AC (Fischer, B. M. & Voynow, 2002, Am.J. Respir. Cell Biol., 26, 447-452). Aerosol administration of NE toguinea pigs produces extensive epithelial damage within 20 minutes ofcontact (Suzuki et al., 1996, Am. J. Resp. Crit. Care Med., 153,1405-1411). Furthermore NE reduces the ciliary beat frequency of humanrespiratory epithelium in vitro (Smallman et al., 1984, Thorax, 39,663-667) which is consistent with the reduced mucociliary clearance thatis seen in COPD patients (Currie et al., 1984, Thorax, 42, 126-130). Theinstillation of NE into the airways leads to mucus gland hyperplasia inhamsters (Lucey et al., 1985, Am. Resp. Crit. Care Med., 132, 362-366).A role for NE is also implicated in mucus hypersecretion in asthma. Inan allergen sensitised guinea pig acute asthma model an inhibitor of NEprevented goblet cell degranulation and mucus hypersecretion (Nadel etal., 1999, Eur. Resp. J., 13, 190-196).

NE has been also shown to play a role in the pathogenesis of pulmonaryfibrosis. NE: α₁-protenase inhibitor complex is increased in serum ofpatients with pulmonary fibrosis, which correlates with the clinicalparameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11,120-125). In a murine model of human pulmonary fibrosis, a NE inhibitorreduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am.J. Resp. Crit. Care Med., 156, 260-265). Furthermore investigators haveshown that NE deficient mice are resistant to bleomycin-inducedpulmonary fibrosis (Dunsmore et al., 2001, Chest, 120, 35S-36S). PlasmaNE level was found to be elevated in patients who progressed to ARDSimplicating the importance of NE in early ARDS disease pathogenesis.(Donnelly et al., 1995, Am. J. Res. Crit. Care Med;, 151, 428-1433). Theantiproteases and NE complexed with antiprotease are increased in lungcancer area (Marchandise et al., 1989, Eur. Resp. J. 2, 623-629). Recentstudies have shown that polymorphism in the promoter region of the NEgene are associated with lung cancer development (Taniguchi et al.,2002, Clin. Cancer Res., 8, 1115-1120.

Acute lung injury caused by endotoxin in experimental animals isassociated with elevated levels of NE (Kawabata, et al., 1999, Am. J.Resp. Crit. Care, 161, 2013-2018). Acute lung inflammation caused byintratracheal injection of lipopolysaccharide in mice has been shown toelevate the NE activity in bronchoalveolar lavage fluid which issignificantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J.Pharmacol., 374, 117-125; Yasui, et al., 1995, Eur. Resp. J., 8,1293-1299). NE also plays an important role in the neutrophil-inducedincrease of pulmonary microvascular permeability observed in a model ofacute lung injury caused by tumour necrosis factor α (TNFα) and phorbolmyristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki etal., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).

A role for NE has also been suggested in monocrotoline-induced pulmonaryvascular wall thickening and cardiac hypertrophy (Molteni et al., 1989,Biochemical Pharmacol. 38, 2411-2419). Serine elastase inhibitorreverses the monocrotaline-induced pulmonary hypertension andremodelling in rat pulmonary arteries (Cowan et al., 2000, NatureMedicine, 6, 698-702). Recent studies have shown that serine elastase,that is, NE or vascular elastase are important in cigarettesmoke-induced muscularisation of small pulmonary arteries in guinea pigs(Wright et al., 2002, Am. J. Respir. Crit. Care Med., 166, 954-960).

NE plays a key role in experimental cerebral ischemic damage (Shimakuraet al., 2000, Brain Research, 858, 55-60), ischemia-reperfusion lunginjury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) andmyocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. J.Physiol., 433, 563-570). Human NE levels in plasma are significantlyincreased above normal in inflammatory bowel diseases, for example,Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26,1306-1311). In addition NE has also been assumed to be involved in thepathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol.Int., 6, 57). The development of collagen induced arthritis in mice issuppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol.165, 26-32).

Thus, human NE is known as one of the most destructive serine proteasesand has been implicated in a variety of inflammatory diseases. Theimportant endogenous inhibitor of human NE is α₁-antitrypsin. Theimbalance between human NE and antiprotease is believed to give rise toan excess of human NE resulting in uncontrolled tissue destruction. Theprotease/antiprotease balance may be upset by a decreased availabilityof α₁-antitrypsin either through inactivation by oxidants such ascigarette smoke, or as a result of genetic inability to producesufficient serum levels. Human NE has been implicated in the promotionor exacerbation of a number of diseases such as pulmonary emphysema,pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemiareperfusion injury, rheumatoid arthritis and pulmonary hypertension.

WO 02/053543 discloses pyridone derivatives having affinity forcannabinoid 2-type receptor.

The present invention discloses novel quinoline derivatives that areinhibitors of human neutrophil elastase and homologous serine proteasessuch as proteinase 3 and pancreatic elastase, and are thereby useful intherapy.

DISCLOSURE OF THE INVENTION

The present invention provides a compound of formula (I)

wherein

R¹ represents H, halogen, CN, C1 to 6 alkyl, C1 to 6 alkoxy, CO₂R⁷ orCONR⁸R9;

R³ represents H or F;

G¹ represents phenyl or a five- or six-membered heteroaromatic ringcontaining 1 to 3 heteroatoms independently selected from O, S and N;

R⁵ represents H, halogen, C1 to 6 alkyl, CN, C1 to 6 alkoxy, NO₂,NR¹⁴R¹⁵, C1 to 3 alkyl substituted by one or more F atoms or C1 to 3alkoxy substituted by one or more F atoms;

R¹⁴ and R¹⁵ independently represent H or C1 to 3 alkyl; said alkyl beingoptionally further substituted by one or more F atoms;

n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R⁵group is selected independently;

R⁴ represents H or C1 to 6 alkyl; said alkyl being optionally furthersubstituted by OH or C1 to 6 alkoxy;

or R⁴ and L are joined together such that the group —NR⁴L represents a 5to 7 membered azacyclic ring optionally incorporating one furtherheteroatom selected from O, S and NR¹⁶;

L represents a bond, O, NR²⁹ or C1 to 6 alkyl; said alkyl beingoptionally incorporating a heteroatom selected from O, S and NR¹⁶; andsaid alkyl being optionally further substituted by OH or OMe;

G² represents a monocyclic ring system selected from:

-   -   i) phenyl or phenoxy,    -   ii) a 5 or 6 membered heteroaromatic ring containing one to        three heteroatoms independently selected from O, S and N,    -   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or    -   iv) a C4 to 7 saturated or partially unsaturated heterocyclic        ring containing one or two heteroatoms independently selected        from O, S(O)_(p) and NR¹⁷ and optionally further incorporating a        carbonyl group; or

G represents a bicyclic ring system in which each of the two rings isindependently selected from:

-   -   i) phenyl,    -   ii) a 5 or 6 membered heteroaromatic ring containing one to        three heteroatoms independently selected from O, S and N,    -   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or    -   iv) a C4 to 7 saturated or partially unsaturated heterocyclic        ring containing one or two heteroatoms independently selected        from O, S(O)_(p) and NR¹⁷ and optionally further incorporating a        carbonyl group;

and the two rings are either fused together, or are bonded directlytogether or are separated by a linker group selected from O, S(O)_(q) orCH₂,

said monocyclic or bicyclic ring system being optionally furthersubstituted by one to three substituents independently selected from CN,OH, C1 to 6 alkyl, C1 to 6 alkoxy, halogen, NR¹⁸R¹⁹, NO₂, OSO₂R³⁸,CO₂R²⁰, C(═NH)NH₂, C(O)NR²¹R²², C(S)NR^(23 R) ²⁴, SC(═NH)NH₂,NR³¹C(═NH)NH₂, S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, C1 to 3 alkoxy substituted byone or more F atoms and C1 to 3 alkyl substituted by SO₂R³⁹ or by one ormore F atoms; or

when L does not represent a bond, G² may also represent H;

p, q, s and t independently represent an integer 0, 1 or 2;

R⁸ and R⁹ independently represent H or C1 to 6 alkyl; or the group NR⁸R⁹together represents a 5 to 7 membered azacyclic ring optionallyincorporating one further heteroatom selected from O, S and NR²⁸;

R¹⁸ and R¹⁹ independently represent H, C1 to 6 alkyl, formyl, C2 to 6alkanoyl, S(O)_(t)R³² or SO₂NR³³R³⁴; said alkyl group being optionallyfurther substituted by halogen, CN, C1 to 4 alkoxy or CONR⁴¹R⁴²;

R²⁵ represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl; said alkyl groupbeing optionally further substituted by one or more substituentsselected independently from OH, CN, CONR³⁵R³⁶, CO₂R³⁷, OCOR⁴⁰, C3 to 6cycloalkyl, a C4 to 7 saturated heterocyclic ring containing one or twoheteroatoms independently selected from O, S(O)_(p) and NR⁴³ and phenylor a 5 or 6 membered heteroaromatic ring containing one to threeheteroatoms independently selected from O, S and N; said aromatic ringbeing optionally further substituted by one or more substituentsselected independently from halogen, CN, C1 to 4 alkyl, C1 to 4 alkoxy,OH, CONR⁴⁴R⁴⁵, CO2R⁴⁶, S(O)_(s)R²⁵ or NHCOCH₃;

R³² represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;

R⁷, R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴, R²⁶, R²⁷, R²⁸, R²⁹, R³¹, R³³,R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵ and R⁴⁶independently represent H or C1 to 6 alkyl;

and pharmaceutically acceptable salts thereof.

The compounds of formula (I) may exist in enantiomeric and/or tautomericforms. It is to be understood that all enantiomers, diastereomers,racemates, tautomers and mixtures thereof are included within the scopeof the invention.

Unless otherwise indicated, the term “C1 to 6 alkyl” referred to hereindenotes a straight or branched chain alkyl group having from 1 to 6carbon atoms. Examples of such groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl. The terms “C1 to3 alkyl” and “C1 to 4 alkyl” are to be interpreted analogously.

Examples of “C1 to 3 alkyl substituted by one or more F atoms” includefluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,1,1-difluoroethyl, pentafluoroethyl and 3,3,3-trifluoropropyl.

Unless otherwise indicated, the term “C1 to 6 alkoxy ” referred toherein denotes an oxygen substituent bonded to a straight or branchedchain alkyl group having from 1 to 6 carbon atoms. Examples of suchgroups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxyand s-butoxy. The terms “C1 to 3 alkoxy” and “C1 to 4 alkoxy” are to beinterpreted analogously.

Examples of “C1 to 3 alkoxy substituted by one or more F atoms” includefluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and3,3,3-trifluoropropoxy.

Unless otherwise indicated, the term “C2 to 6 alkanoyl” referred toherein denotes a straight or branched chain alkyl group having from 1 to5 carbon atoms bonded to the molecule via a carbonyl group. Examples ofsuch groups include acetyl, propionyl and pivaloyl.

Unless otherwise indicated, the term “halogen” referred to hereindenotes fluorine, chlorine, bromine and iodine.

Examples of a five or six membered heteroaromatic ring containing 1 to 3heteroatoms independently selected from O, S and N include furan,thiophene, pyrrole, oxazole, oxadiazole, isoxazole, imidazole, thiazole,triazole, thiadiazole, pyridine, pyrimidine and pyrazine.

Unless otherwise indicated, the term “C3 to 6 saturated or partiallyunsaturated cycloalkyl” referred to herein denotes a 3 to 6 memberednon-aromatic carbocyclic ring optionally incorporating one or moredouble bonds. Examples include cyclopropyl, cyclopentyl, cyclopentenyl,cyclohexyl and cyclohexenyl. The term “five- or six-membered saturatedor partially unsaturated cycloalkyl ring” is to be interpretedanalogously.

Unless otherwise indicated, the term “C4 to 7 saturated or partiallyunsaturated heterocyclic ring containing one or two heteroatomsindependently selected from O, S(O)_(p) and NR¹⁷ and optionally furtherincorporating a carbonyl group” referred to herein denotes a 4 to 7membered non-aromatic heterocyclic ring optionally incorporating one ormore double bonds and optionally incorporating a carbonyl group.Examples include tetrahydrofuran, thiolane 1,1-dioxide, tetrahydropyran,4-oxo-4H-pyran, pyrrolidine, pyrroline, imidazolidine, 1,3-dioxolane,piperidine, piperazine, morpholine, perhydroazepine, pyrrolidone andpiperidone. The term “five- or six-membered saturated or partiallyunsaturated heterocyclic ring containing one heteroatom selected from O,S and NR¹³” is to be interpreted analogously.

Examples of a “5 to 7 membered azacyclic ring optionally incorporatingone further heteroatom selected from O, S and NR¹⁶” include pyrrolidine,piperidine, morpholine, thiomorpholine and piperazine.

In the definition of L, “C1 to 6 alkyl; said alkyl optionallyincorporating a heteroatom selected from O, S and NR¹⁶” embraces astraight or branched chain arrangement of 1 to 6 carbon atoms in whichany two carbon atoms are optionally separated by O, S or NR¹⁶. Thedefinition thus includes, for example, methylene, ethylene, propylene,hexamethylene, ethylethylene, —CH₂CH₂O—CH₂—, —CH₂CH₂O—CH₂—CH₂—,—CH₂CH₂S— and —CH₂CH₂NR¹⁶—.

Examples of bicyclic ring systems in which the two rings are eitherfused together, or are bonded directly together or are separated by alinker group selected from O, S(O)_(q) or CH₂ include biphenyl,thienylphenyl, pyrazolylphenyl, phenoxyphenyl, naphthyl, indanyl,quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl,indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl,benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl, quinazolyl,quinoxalyl, chromanyl, isocromanyl, 3H-indolyl, 1H-indazolyl,quinuclidyl, tetrahydronaphthyl, dihydrobenzofuranyl,morpholine-4-ylphenyl, 1,3-benzodioxolyl,1,1-dioxido-2,3-dihydro-1-benzothienyl, 2,3-dihydro-1,4-benzodioxinyland 3,4-dihydro-isochromenyl.

In one embodiment, R¹ in formula (I) represents H.

In one embodiment, R³ in formula (I) represents H.

In one embodiment, G¹ in formula (I) represents phenyl or pyridyl. Inanother embodiment, G¹ in formula (1) represents phenyl.

In one embodiment, R⁵ in formula (I) represents halogen, C1 to 6 alkyl,CN or C1 to 3 alkyl substituted by one or more F atoms. In anotherembodiment, R⁵ in formula (I) represents Cl, CH₃, CN or CF₃.

In one embodiment, n represents the integer 1.

In another embodiment, G¹ in formula (I) represents phenyl, R⁵represents CF₃ and n represents the integer 1.

In one embodiment, R⁴ represents H.

In one embodiment, L represents C1 to 6 alkyl. In another embodiment, Lrepresents —CH₂—. In another embodiment, L represents NR²⁹ and R²⁹represents H.

In one embodiment, G² represents an optionally substituted monocyclicring system selected from:

-   -   i) phenyl,    -   ii) a 5 or 6 membered heteroaromatic ring containing one to        three heteroatoms independently selected from O, S and N,    -   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or        p1 iv) a C4 to 7 saturated or partially unsaturated heterocyclic        ring containing one or two heteroatoms independently selected        from O, S(O)_(p) and NR and optionally further incorporating a        carbonyl group.

In another embodiment, G² represents optionally substituted phenyl. Inanother embodiment, G² represents phenyl substituted by OSO₂R³⁸,S(O)_(s)R²⁵, SO₂NR²⁶R²⁷, NR¹⁸R¹⁹ (wherein at least one of R¹⁸ and R¹⁹represents S(O)_(t)R³² or SO2NR³³R³⁴) or C1 to 3 alkyl substituted bySO₂R³⁹.

In another embodiment, G² represents an optionally substituted bicyclicring system in which each of the two rings is independently selectedfrom:

-   -   i) phenyl,    -   ii) a 5 or 6 membered heteroaromatic ring containing one to        three heteroatoms independently selected from O, S and N,    -   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or    -   iv) a C4 to 7 saturated or partially unsaturated heterocyclic        ring containing one or two heteroatoms independently selected        from O, S(O)_(p) and NR¹⁷ and optionally further incorporating a        carbonyl group;

and the two rings are either fused together, or are bonded directlytogether or are separated by a linker group selected from O, S(O)_(q) orCH₂.

In one embodiment, R¹ in formula (I) represents H; G¹ represents phenyl;R⁵ represents halogen, C1 to 6 alkyl, CN or C1 to 3 alkyl substituted byone or more F atoms; R⁴ represents H; L represents C1 to 6 alkyl; and G²represents an optionally substituted monocyclic ring system selectedfrom:

-   -   i) phenyl,    -   ii) a 5 or 6 membered heteroaromatic ring containing one to        three heteroatoms independently selected from O, S and N,    -   iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or    -   iv) a C4 to 7 saturated or partially unsaturated heterocyclic        ring containing one or two heteroatoms independently selected        from O, S(O)_(p) and NR¹⁷ and optionally further incorporating a        carbonyl group.

In another aspect, the invention specifically provides any compound asdescribed in the Examples herein, or the free base thereof or apharmaceutically acceptable salt thereof.

Particular compounds include:

-   N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide,-   N-(cyclohexylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2-furylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(3,4-dimethoxyphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(3-morpholin-4-ylpropyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-(1-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2-methoxybenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(4-methoxyphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-(2-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(4-bromobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2-bromobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-[(2R)-2-phenylcyclopropyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(3-chlorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(4-cyanocyclohexyl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[3-(2-methylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(1-naphthylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(3-methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2-chlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(4-methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(4-fluorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(1,3-benzodioxol-5-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2,4-dichlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(4-chlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(4-methoxybenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(3-chlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(3,4-difluorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2-chloro-4-fluorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(3,4-dichlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(2-methoxyphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(4-fluorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(3-fluorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(2-fluorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2-cyclohex-1-en-1-ylethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-3-carboxamide;-   N-(3-methoxybenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[1-(4-chlorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2,5-difluorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-(pyridin-4-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   methyl    4-{[({2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinolin-3-yl}carbonyl)amino]methyl}benzoate;-   2-oxo-N-[2-(2-thienyl)ethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-(4-phenoxybenzyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N′-(4-cyanophenyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carbohydrazide;-   2-oxo-N-(3-thienylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(4-methylphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-{2-[4-(aminosulfonyl)phenyl]ethyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-phenoxy-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(6-fluoro-4H-1,3-benzodioxin-8-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(1-benzothien-3-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(4-benzylmorpholin-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(1-methyl-1H-imidazol-4-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[2-(1-methyl-1H-imidazol-5-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-{[3-(4-methoxyphenyl)isoxazol-5-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[3-(3,5-dimethyl-1H-pyrazol-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-{[1-(3-methylphenyl)-1H-pyrazol-4-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[3-(2-ethylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(5-methoxy-4-oxo-4H-pyran-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-(3-azepan-1-ylpropyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[4-(acetylamino)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-[3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[3-(4-methylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   2-oxo-N-(3-piperidin-1-ylpropyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide;-   N′-[4-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carbohydrazide;

The present invention includes compounds of formula (I) in the form ofsalts, in particular acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

In a further aspect the invention provides a process for the preparationof a compound of is formula (I) which comprises reacting a compound offormula (II)

wherein R¹, R³, R⁵, G¹ and n are as defined in formula (I) and L¹represents a leaving group,

with an amine of formula (III) or a salt thereof

wherein R⁴, G² and L are as defined in formula (I),

and where desired or necessary converting the resultant compound offormula (I), or another salt thereof, into a pharmaceutically acceptablesalt thereof; or converting one compound of formula (I) into anothercompound of formula (I); and where desired converting the resultantcompound of formula (I) into an optical isomer thereof.

The process is carried out at a suitable temperature, generally between0° C. and the boiling point of the solvent, in a suitable solvent suchas dichloromethane, dioxan or N-methylpyrrolidinone. The process isoptionally carried out in the presence of a base and/or a couplingreagent such as HATU, HOAT, HOBT or DIEA. Suitable leaving groups L¹include OH and halogen, particularly OH or Cl.

Compounds of formula (II) wherein L¹ represents OH may be prepared usingmethods that will be readily apparent to the man skilled in the art.See, for example, JP 46015097.

Salts of compounds of formula (I) may be formed by reacting the freebase or a salt, enantiomer, tautomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble, orin a solvent in which the salt is soluble followed by subsequent removalof the solvent in vacuo or by freeze drying. Suitable solvents include,for example, water, dioxane, ethanol, 2-propanol, tetrahydrofuran ordiethyl ether, or mixtures thereof. The reaction may be a metatheticalprocess or it may be carried out on an ion exchange resin.

Compounds of formula (I) and intermediate compounds thereto may beprepared as such or in protected form. The protection and deprotectionof functional groups is, for example, described in ‘Protective Groups inOrganic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’, 3rd edition, T. W. Greene & P.G. M. Wuts, Wiley-Interscience (1999).

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures, and if necessary further purified, by usingstandard techniques.

The compounds of formula (I) may exist in enantiomeric ordiastereoisomeric forms or mixtures thereof, all of which are includedwithin the scope of the invention. The various optical isomers may beisolated by separation of a racemic mixture of the compounds usingconventional techniques, for example, fractional crystallisation orHPLC. Alternatively, the individual enantiomers may be made by reactionof the appropriate optically active starting materials under reactionconditions that will not cause racemisation.

Intermediate compounds may also exist in enantiomeric forms and may beused as purified enantiomers, diastereomers, racemates or mixturesthereof.

According to a further aspect of the invention we provide a compound offormula (I) or a pharmaceutically acceptable salt thereof, for use as amedicament.

The compounds of formula (I), and their pharmaceutically acceptablesalts, are useful because they possess pharmacological activity inanimals. The compounds of formula (I) have activity as pharmaceuticals,in particular as modulators of human neutrophil elastase and homologousserine proteases such as proteinase 3 and pancreatic elastase, and assuch are predicted to be useful in therapy. The compounds of formula (I)are particularly useful as inhibitors of human neutrophil elastase. Theymay thus be used in the treatment or prophylaxis of inflammatorydiseases and conditions.

Examples of these conditions are: adult respiratory distress syndrome(ARDS), cystic fibrosis, pulmonary emphysema, chronic obstructivepulmonary disease (COPD) and ischaemic-reperfusion injury. The compoundsof this invention may also be useful in the modulation of endogenousand/or exogenous biological irritants which cause and/or propagateatherosclerosis, diabetes, myocardial infarction; hepatic disordersincluding but not limited to cirrhosis, systemic lupus erythematous,inflammatory disease of lymphoid origin, including but not limited to Tlymphocytes, B lymphocytes, thymocytes; autoimmune diseases, bonemarrow; inflammation of the joint (especially rheumatoid arthritis,osteoarthritis and gout); inflammation of the gastrointestinal tract(especially inflammatory bowel disease, ulcerative colitis, pancreatitisand gastritis); inflammation of the skin (especially psoriasis, eczema,dermatitis); in tumour metastasis or invasion; in disease associatedwith uncontrolled degradation of the extracellular matrix such asosteoarthritis; in bone resorptive disease (such as osteoporosis andPaget's disease); diseases associated with aberrant angiogenesis; theenhanced collagen remodelling associated with diabetes, periodontaldisease (such as gingivitis), corneal ulceration, ulceration of theskin, post-operative conditions (such as colonic anastomosis) and dermalwound healing; demyelinating diseases of the central and peripheralnervous systems (such as multiple sclerosis); age related illness suchas dementia, inflammatory diseases of cardiovascular origins;granulomatous diseases; renal diseases including but not limited tonephritis and polyarteritis; cancer; pulmonary hypertension, ingestedpoisons, skin contacts, stings, bites; asthma; rhinitis; HIV diseaseprogression; for minimising the effects of organ rejection in organtransplantation including but not limited to human organs; andreplacement therapy of proteinase inhibitors.

Thus, another aspect of the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment or prophylaxis of diseasesor conditions in which inhibition of neutrophil elastase activity isbeneficial; and a method of treating, or reducing the risk of, diseasesor conditions in which inhibition of neutrophil elastase activity isbeneficial which comprises administering to a person suffering from orat risk of, said disease or condition, a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment or prophylaxis ofinflammatory diseases or conditions; and a method of treating, orreducing the risk of, inflammatory diseases or conditions whichcomprises administering to a person suffering from or at risk of, saiddisease or condition, a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

In particular, the compounds of this invention may be used in thetreatment of adult respiratory distress syndrome (ARDS), cysticfibrosis, pulmonary emphysema, chronic obstructive pulmonary disease(COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperfusioninjury, rheumatoid arthritis, osteoarthritis, cancer, atherosclerosisand gastric mucosal injury.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

For the above mentioned therapeutic indications, the dose of thecompound to be administered will depend on the compound employed, thedisease being treated, the mode of administration, the age, weight andsex of the patient. Such factors may be determined by the attendingphysician. However, in general, satisfactory results are obtained whenthe compounds are administered to a human at a daily dosage of between0.1 mg/kg to 100 mg/kg (measured as the active ingredient).

The compounds of formula (I) may be used on their own, or in the form ofappropriate pharmaceutical formulations comprising the compound of theinvention in combination with a pharmaceutically acceptable diluent,adjuvant or carrier. Particularly preferred are compositions notcontaining material capable of causing an adverse reaction, for example,an allergic reaction. Conventional procedures for the selection andpreparation of suitable pharmaceutical formulations are described in,for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E.Aulton, Churchill Livingstone, 1988.

According to the invention, there is provided a pharmaceuticalformulation comprising preferably less than 95% by weight and morepreferably less than 50% by weight of a compound of formula (I) inadmixture with a pharmaceutically acceptable diluent or carrier.

We also provide a method of preparation of such pharmaceuticalformulations that comprises mixing the ingredients.

The compounds may be administered topically, for example, to the lungsand/or the airways, in the form of solutions, suspensions, HFA aerosolsor dry powder formulations, for example, formulations in the inhalerdevice known as the Turbuhaler®; or systemically, for example, by oraladministration in the form of tablets, pills, capsules, syrups, powdersor granules; or by parenteral administration, for example, in the formof sterile parenteral solutions or suspensions; or by rectaladministration, for example, in the form of suppositories.

Dry powder formulations and pressurized HFA aerosols of the compounds ofthe invention may be administered by oral or nasal inhalation. Forinhalation, the compound is desirably finely divided. The finely dividedcompound preferably has a mass median diameter of less than 10 μm, andmay be suspended in a propellant mixture with the assistance of adispersant, such as a C₈-C₂₀ fatty acid or salt thereof, (for example,oleic acid), a bile salt, a phospholipid, an alkyl saccharide, aperfluorinated or polyethoxylated surfactant, or other pharmaceuticallyacceptable dispersant.

The compounds of the invention may also be administered by means of adry powder inhaler. The inhaler may be a single or a multi dose inhaler,and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound with a carriersubstance, for example, a mono-, di- or polysaccharide, a sugar alcohol,or an other polyol. Suitable carriers are sugars, for example, lactose,glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose,mannitol; and starch. Alternatively the finely divided compound may becoated by another substance. The powder mixture may also be dispensedinto hard gelatine capsules, each containing the desired dose of theactive compound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, forexample, that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive compound, with or without a carrier substance, is delivered tothe patient.

For oral administration the active compound may be admixed with anadjuvant or a carrier, for example, lactose, saccharose, sorbitol,mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum, titanium dioxide, and the like. Alternatively, thetablet may be coated with a suitable polymer dissolved in a readilyvolatile organic solvent.

For the preparation of soft gelatine capsules, the compound may beadmixed with, for example, a vegetable oil or polyethylene glycol. Hardgelatine capsules may contain granules of the compound using either theabove mentioned excipients for tablets. Also liquid or semisolidformulations of the drug may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing the compound, the balancebeing sugar and a mixture of ethanol, water, glycerol and propyleneglycol. Optionally such liquid preparations may contain colouringagents, flavouring agents, saccharine and/or carboxymethylcellulose as athickening agent or other excipients known to those skilled in art.

The compounds of the invention may also be administered in conjunctionwith other compounds used for the treatment of the above conditions.

The following Examples are intended to illustrate, but in no way limitthe scope of the invention.

General Procedures

¹H NMR spectra were recorded on a Varian Mercury-VX 300 MHz instrument.The central peak of dimethylsulfoxide-d₆ (δ_(H) 2.50 ppm) was used asinternal reference. Column chromatography was carried out using silicagel (0.040-0.063 mm, Merck). Unless stated otherwise, starting materialswere commercially available. All solvents and commercial reagents wereof laboratory grade and were used as received. Unless otherwise stated,organic solutions were dried using anhydrous Na₂SO₄.

LC-MS Conditions : Instrument Agilent 1100; Column: Waters Symmetry2.1×30 mm; C18 3.5 μm; Mass APCI; Flow rate 0.7 ml/min; Wavelength 254nm; Solvent A: water +0.1% TFA; solvent B: acetonitrile +0.1% TFA;Gradient 15-95%/B 8 min, 95% B 1 min; retention times (RT) are recordedin minutes.

The following abbreviations are used:

HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

HOAT 1-Hydroxy-7-azabenzotriazole

DIEA N,N-Diisopropylethylamine

NMP 1-N-Methyl-2-pyrrolidinone

DMF N,N-dimethylformamide

EXAMPLE 1.1N-[4-(Methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamidea) 2-Oxo-1-[-(trifluoromethyl)phenyl]-1,2-dihydroquinolie-3-carboxylicacid

The title compound was prepared by analogy to the procedure disclosed inJP 46015097.

¹H NMR (DMSO-d₆): δ 14.01 (1H, s); 9.09 (1H, s); 8.18 (1H, d); 8.01 (2H,d); 7.93 (1H, t); 7.84 (1H, d); 7.68 (1H, t); 7.47 (1H, t); 6.65 (1H,d).

b) 2-Oxo-1-[-(trifluoromethyl)phenyl]-1,2-dihydroquinolie-3-carbonylchloride

To a solution of2-oxo-1-[-(trifluoromethyl)phenyl]-1,2-dihydroquinolie-3-carboxylic acid(5 g, 15 mmol) in dichloromethane (100 ml), oxalyl chloride (20 ml) andDMF (2 drops) were added. The mixture was stirred at ambient temperaturefor 15 h. The solvent was evaporated and the crude product was usedwithout purification. Yield 5.3 g.

¹H NMR (CDCl₃): δ 8.90 (1H, s); 7.83 (2H, m); 7.77 (1H, t); 7.57 (2H,m); 7.51 (1H, d); 7.35 (1H, t); 6.64 (1H, d).

c)N-[4-(Methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

A solution of [4-(methylsulfonyl)benzyl]amine hydrochloride (67 mg, 0.30mmol) and DIEA (154 μl, 0.90 mmol) in dioxan (2 ml) was added to asolution of2-oxo-1-[-(trifluoromethyl)phenyl]-1,2-dihydroquinolie-3-carbonylchloride in dioxan (3 ml). The mixture was stirred for 4 h and thendiluted with water (4 ml). This solution was then purified bypreparative HPLC to give the title compound (80 mg, 57%).

¹H NMR (DMSO-d₆): δ 9.99 (1H, t); 9.01 (1H, s); 8.10 (1H, d); 8.02-7.75(6H, m); 7.58 (3H, d); 7.38 (1H, t); 6.57 (1H, d); 4.64 (2H, d); 3.18(3H, s).

Using the appropriate amine or a salt thereof, the following compoundswere prepared by a method analogous to that described in Example 1.1.

EXAMPLE 2.1N-(Cyclohexylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.59 min, m/z 429.2 [MH⁺].

EXAMPLE 2.2N-(2-Furylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.52 min, m/z 413.2 [MH⁺].

EXAMPLE 2.3N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.56 min, m/z 497.2 [MH⁺].

EXAMPLE 2.42-Oxo-N-(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.56 min, m/z 424.2 [MH⁺].

EXAMPLE 2.5N-(3-Morpholin-4-ylpropyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.56 min, m/z 460.2 [MH⁺].

EXAMPLE 2.62-Oxo-N-(1-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.14 min, m/z 437.2 [MH⁺].

EXAMPLE 2.7N-(2-Methoxybenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.95 min, m/z 453.2 [MH⁺].

EXAMPLE 2.8N-[2-(4-Methoxyphenyl)ethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.95 min, m/z 467.2 [MH⁺].

EXAMPLE 2.92-Oxo-N-(2-phenylethyl)-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.04 min, m/z 437.2 [MH⁺].

EXAMPLE 2.10N-(4-Bromobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.44 min, m/z 501.1 [MH⁺].

EXAMPLE 2.11N-(2-Bromobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.33 min, m/z 501.1 [MH⁺].

EXAMPLE 2.122-Oxo-N-[(2R)-2-phenylcyclopropyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.34 min, m/z 449.2 [MH⁺].

EXAMPLE 2.13N-[2-(3-Chlorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.41 min, m/z 471.2 [MH⁺].

EXAMPLE 2.14N-[(4-Cyanocyclohexyl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.50 min m/z 454.2 [MH⁺].

EXAMPLE 2.15N-[3-(2-Methylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.88 min, m/z 472.3 [MH⁺].

EXAMPLE 2.16N-(1-Naphthylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.43 min, m/z 473.2 [MH⁺].

EXAMPLE 2.17N-(3-Methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.20 min, m/z 437.2 [MH⁺].

EXAMPLE 2.18N-(2-Chlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.24 min, m/z 457.2 [MH⁺].

EXAMPLE 2.19N-(4-Methylbenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.20 min, m/z 437.2 [MH⁺].

EXAMPLE 2.20N-(4-Fluorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.97 min, m/z 441.2 [MH⁺].

EXAMPLE 2.21N-(1,3-Benzodioxol-5-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.74 min, m/z 467.2 [MH⁺].

EXAMPLE 2.22N-(2,4-Dichlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.78 min, m/z 491.1 [MH⁺].

EXAMPLE 2.23N-(4-Chlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.33 min, m/z 457.1 [MH⁺].

EXAMPLE 2.24N-(4-Methoxybenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.80 min, m/z 453.2 [MH⁺].

EXAMPLE 2.25N-(3-Chlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.31 min, m/z 457.1 [MH⁺].

EXAMPLE 2.26N-(3,4-Difluorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.12 min, m/z 459.2 [MH⁺].

EXAMPLE 2.27N-(2-Chloro-4-fluorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.38 min, m/z 475.2 [MH⁺].

EXAMPLE 2.28N-(3,4-Dichlorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.70 min, m/z 491.1 [MH⁺].

EXAMPLE 2.29N-[2-(2-Methoxyphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.13 min, m/z 467.2 [MH⁺].

EXAMPLE 2.30N-[2-(4-Fluorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.09 min, m/z 455.2 [MH⁺].

EXAMPLE 2.31N-[2-(3-Fluorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.09 min, m/z 455.2 [MH⁺].

EXAMPLE 2.32N-[2-(2-Fluorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.08 min, m/z 455.2 [MH⁺].

EXAMPLE 2.33N-(2-Cyclohex-1-en-1-ylethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.64 min, m/z 441.2 [MH⁺].

EXAMPLE 2.34N-(3-Methoxybenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.85 min, m/z 453.2 [MH⁺].

EXAMPLE 2.35N-[1-(4-Chlorophenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.58 min, m/z 471.2 [MH⁺].

EXAMPLE 2.36N-(2,5-Difluorobenzyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.84 min, m/z 459.2 [MH⁺].

EXAMPLE 2.372-Oxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.36 min, m/z 458.2 [MH⁺].

EXAMPLE 2.382-Oxo-N-(pyridin-4-ylmethyl)-1-[3-(trifluoromethyl)phenyl-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.57 min, m/z 424.2 [MH⁺].

EXAMPLE 2.39N-(2,3-Dihydro-1-benzofuran-5-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.78 min, m/z 465.2 [MH⁺].

EXAMPLE 2.40 Methyl4-{[({2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinolin-3-yl}carbonyl)amino]methyl}benzoate

LC-MS RT: 5.76 min, m/z 481.2 [MH⁺].

EXAMPLE 2.412-Oxo-N-[2-(2-thienyl)ethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.89 min, m/z 443.2 [MH⁺].

EXAMPLE 2.422-Oxo-N-(4-phenoxybenzyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.80 min, m/z 515.2 [MH⁺].

EXAMPLE 2.43N′-(4-Cyanophenyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carbohydrazide

LC-MS RT: 5.36 min, m/z 449.2 [MH⁺].

EXAMPLE 2.442-Oxo-N-(3-thienylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.76 min, m/z 429.1 [MH⁺].

EXAMPLE 2.45N-[(5-Methylisoxazol-3-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.18 min, m/z 428.2 [MH⁺].

EXAMPLE 2.46N-[2-(4-Methylphenyl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.36 min, m/z 451.2 [MH⁺].

EXAMPLE 2.47N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.86 min, m/z 516.2 [MH⁺].

EXAMPLE 2.482-Oxo-N-[4-(1H-pyrazol-1-yl)benzyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.64 min, m/z 489.2 [MH⁺].

EXAMPLE 2.492-Oxo-N-phenoxy-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.79 min, m/z 425.2 [MH⁺].

EXAMPLE 2.50N-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.71 min, m/z 481.2 [MH⁺].

EXAMPLE 2.51N-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.06 min, m/z 481.3 [MH⁺].

EXAMPLE 2.52N-[(6-Fluoro-4H-1,3-benzodioxin-8-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.86 min, m/z 499.2 [MH⁺].

EXAMPLE 2.53N-(1-Benzothien-3-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.41 min, m/z 479.2 [MH⁺].

EXAMPLE 2.54N-[(4-Benzylmorpholin-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.12 min, m/z 522.3 [MH⁺].

EXAMPLE 2.55N-[2-(1-Methyl-1H-imidazol-4-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.57 min, m/z 441.2 [MH⁺].

EXAMPLE 2.56N-[2-(1-Methyl-1H-imidazol-5-yl)ethyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.59 min, m/z 441.2 [MH⁺].

EXAMPLE 2.57N-{[3-(4-Methoxyphenyl)isoxazol-5-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.04 min, m/z 520.2 [MH⁺].

EXAMPLE 2.582-Oxo-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.17 min, m/z 445.2 [MH⁺].

EXAMPLE 2.59N-[3-(3,5-Dimethyl-1H-pyrazol-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.09 min, m/z 469.2 [MH⁺].

EXAMPLE 2.60N-[(1-Methyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.44 min, m/z 427.2 [MH⁺].

EXAMPLE 2.612-Oxo-N-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 5.76 min, m/z 489.2 [MH⁺].

EXAMPLE 2.62N-{[1-(3-Methylphenyl)-1H-pyrazol-4-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 6.08 min, m/z 503.2 [MH⁺].

EXAMPLE 2.63N-[3-(2-Ethylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.06 min, m/z 486.3 [MH⁺].

EXAMPLE 2.64N-[(5-Methoxy-4-oxo-4H-pyran-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.37 min, m/z 471.2 [MH⁺].

EXAMPLE 2.65N-(3-Azepan-1-ylpropyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.94 min, m/z 472.3 [MH⁺].

EXAMPLE 2.66N-[4-(Acetylamino)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.79 min, m/z 480.2 [MH⁺].

EXAMPLE 2.672-Oxo-N-[3-(5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.96 min, m/z 457.2 [MH⁺].

EXAMPLE 2.68N-[3-(4-Methylpiperidin-1-yl)propyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.59 min, m/z 472.3 [MH⁺].

EXAMPLE 2.69N-[(1,3-Dimethyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.27 min, m/z 441.2 [MH⁺].

EXAMPLE 2.70N-[(1-Ethyl-3-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.46 min, m/z 455.2 [MH⁺].

EXAMPLE 2.71N-[(1-Ethyl-5-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 4.50 min, m/z 455.2 [MH⁺].

EXAMPLE 2.722-Oxo-N-(3-piperidin-1-ylpropyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

LC-MS RT: 3.77 min, m/z 458.3 [MH⁺].

EXAMPLE 2.73N′-[4-(Methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carbohydrazide

LC-MS RT: 4.81 min, m/z 502.2 [MH⁺].

Screen

Human Neutrophil Elastase Quenched-FRET Assay

The assay uses Human Neutrophil Elastase (HNE) purified from serum(Calbiochem art. 324681; Ref. Baugh, R. J. et al., 1976, Biochemistry.15, 836-841). HNE was stored in 50 mM NaOAc, 200 mM NaCl, pH 5.5 withadded 30% glycerol at −20° C. The protease substrate used was ElastaseSubstrate V Fluorogenic, MeOSuc-AAPV-AMC (Calbiochem art. 324740; Ref.Castillo, M. J. et al., 1979, Anal. Biochem. 99, 53-64). The substratewas stored in DMSO at −20° C. The assay additions were as follows: Testcompounds and controls were added to black 96-well flat-bottom plates(Greiner 655076), 1 μL in 100% DMSO, followed by 30 μL HNE in assaybuffer with 0.01% TritonX-100. The assay buffer constitution was: 100 mMTris (pH 7.5) and 500 mM NaCl. The enzyme and the compounds wereincubated at room temperature for 15 minutes. Then 30 μl substrate inassay buffer was added. The assay was stopped after 30 minutesincubation at room temperature by adding 60 μl stop solution (140 mMacetic acid, 200 mM sodium monochloroacetate, 60 mM sodium acetate, pH4.3). Fluorescence was measured on a Wallac 1420 Victor 2 instrument atsettings: Excitation 380 nm, Emission 460 nm. IC₅₀ values weredetermined using Xlfit curve fitting using model 205.

When tested in the above screen, the compounds of the Examples gave IC₅₀values for inhibition of human neutrophil elastase activity of less than30 μM, indicating that the compounds of the invention are expected topossess useful therapeutic properties. Specimen results are shown in thefollowing Table: Inhibition of Human Neutrophil Elastase Compound IC₅₀(nM) Example 2.26 500 Example 2.51 390 Example 2.66 320

1. A compound of formula (I)

wherein R¹ represents H, halogen, CN, C1 to 6 alkyl, C1 to 6 alkoxy,CO₂R⁷ or CONR⁸R⁹; R³ represents H or F; G¹ represents phenyl or a five-or six-membered heteroaromatic ring containing 1 to 3 heteroatomsindependently selected from O, S and N; R⁵ represents H, halogen, C1 to6 alkyl, CN, C1 to 6 alkoxy, NO₂, NR¹⁴R¹⁵, C1 to 3 alkyl substituted byone or more F atoms or C1 to 3 alkoxy substituted by one or more Fatoms; R¹⁴ and R¹⁵ independently represent H or C1 to 3 alkyl; saidalkyl being optionally further substituted by one or more F atoms; nrepresents an integer 1, 2 or 3 and when n represents 2 or 3, each R⁵group is selected independently; R⁴ represents H or C1 to 6 alkyl; saidalkyl being optionally further substituted by OH or C1 to 6 alkoxy; orR⁴ and L are joined together such that the group —NR⁴L represents a 5 to7 membered azacyclic ring optionally incorporating one furtherheteroatom selected from O, S and NR¹⁶; L represents a bond, O, NR²⁹ orC1 to 6 alkyl; said alkyl being optionally incorporating a heteroatomselected from O, S and NR¹⁶; and said alkyl being optionally furthersubstituted by OH or OMe; G² represents a monocyclic ring systemselected from: i) phenyl or phenoxy, ii) a 5 or 6 memberedheteroaromatic ring containing one to three heteroatoms independentlyselected from O, S and N, iii) a C3 to 6 saturated or partiallyunsaturated cycloalkyl, or iv) a C4 to 7 saturated or partiallyunsaturated heterocyclic ring containing one or two heteroatomsindependently selected from O, S(O)_(p) and NR¹⁷ and optionally furtherincorporating a carbonyl group; or G² represents a bicyclic ring systemin which each of the two rings is independently selected from: i)phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one tothree heteroatoms independently selected from O, S and N, iii) a C3 to 6saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7saturated or partially unsaturated heterocyclic ring containing one ortwo heteroatoms independently selected from O, S(O)_(p) and NR¹⁷ andoptionally further incorporating a carbonyl group; and the two rings areeither fused together, or are bonded directly together or are separatedby a linker group selected from O, S(O)_(q) or CH₂, said monocyclic orbicyclic ring system being optionally further substituted by one tothree substituents independently selected from CN, OH, C1 to 6 alkyl, C1to 6 alkoxy, halogen, NR¹⁸R¹⁹, NO₂, OSO₂R³⁸, CO₂R²⁰, C(═NH)NH₂,C(O)NR²¹R²², C(S)NR²³R²⁴, SC(═NH)NH₂, NR³¹C(═NH)NH₂, S(O)_(s)R²⁵,SO₂NR²⁶R²⁷, C1 to 3 alkoxy substituted by one or more F atoms and C1 to3 alkyl substituted by SO₂R³⁹ or by one or more F atoms; or when L doesnot represent a bond, G² may also represent H; p, q, s and tindependently represent an integer 0, 1 or 2; R⁸ and R⁹ independentlyrepresent H or C1 to 6 alkyl; or the group NR⁸R⁹ together represents a 5to 7 membered azacyclic ring optionally incorporating one furtherheteroatom selected from O, S and NR²⁸; R¹⁸ and R¹⁹ independentlyrepresent H, C1 to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)_(t)R³ orSO₂NR³³R³⁴; said alkyl group being optionally further substituted byhalogen, CN, C1 to 4 alkoxy or CONR⁴¹R⁴²; R²⁵ represents H, C1 to 6alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally furthersubstituted by one or more substituents selected independently from OH,CN, CONR³⁵R³⁶; CO₂R³⁷, OCOR⁴⁰, C3 to 6 cycloalkyl, a C4 to 7 saturatedheterocyclic ring containing one or two heteroatoms independentlyselected from O, S(O)_(p) and NR⁴³ and phenyl or a 5 or 6 memberedheteroaromatic ring containing one to three heteroatoms independentlyselected from O, S and N; said aromatic ring being optionally furthersubstituted by one or more substituents selected independently fromhalogen, CN, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CONR⁴⁴R⁴⁵, CO2R⁴⁶,S(O)_(s)R²⁵ or NHCOCH₃; R represents H, C1 to 6 alkyl or C3 to 6cycloalkyl; R⁷, R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴, R²⁶, R²⁷, R²⁸, R²⁹,R³¹, R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵ andR⁴⁶ independently represent H or C1 to 6 alkyl; and pharmaceuticallyacceptable salts thereof.
 2. A compound of formula (I), according toclaim 1, wherein G¹ represents phenyl.
 3. A compound of formula (I),according to claim 1, wherein R⁴ represents H.
 4. A compound of formula(I), according to claim 1, wherein R⁵ represents Cl, CH₃, CN or CF₃. 5.(canceled)
 6. A pharmaceutical formulation comprising a compound offormula (I), as defined in claim 1 or a pharmaceutically acceptable saltthereof, optionally in admixture with a pharmaceutically acceptablediluent or carrier.
 7. A method of treating, or reducing the risk of, ahuman disease or condition in which inhibition of neutrophil elastaseactivity is beneficial which comprises administering to a personsuffering from or susceptible to such a disease or condition, atherapeutically effective amount of a compound of formula (I), asdefined in claim 1, or a pharmaceutically acceptable salt thereof. 8.(canceled)
 9. A method of treating or preventing an inflammatory diseaseor condition, the method comprising administering a therapeuticallyeffective amount of a compound of formula (I) as defined in claim 1, ora pharmaceutically acceptable salt thereof.
 10. A process for thepreparation of a compound of formula (I), as defined in claim 1, andoptical isomers, racemates and tautomers thereof and pharmaceuticallyacceptable salts thereof, which comprises reacting a compound of formula(II)

wherein R¹, R³, R⁵, G¹ and n are as defined in claim 1 and L¹ representsa leaving group, with an amine of formula (III) or a salt thereof

wherein R⁴, G² and L are as defined in claim 1, and where desired ornecessary converting the resultant compound of formula (I), or anothersalt thereof, into a pharmaceutically acceptable salt thereof; orconverting one compound of formula (I) into another compound of formula(I); and where desired converting the resultant compound of formula (I)into an optical isomer thereof.